Process for the production of 18 F-labeled organic compounds by nucleophilic substitution

ABSTRACT

Organic compounds labeled with no-carrier-added fluorine 18 are processed  yield a compound having a formula in the form of  18  F-R through a nucleophilic substitution reaction. The process has a series of steps. The first step of the process relates to providing an organic compound having a formula of X-R. X is the nucleophilic leaving group in the substitution action, and R is a preferred substituted hydrocarbon structure being selected from aliphatic, alicyclic, heterocyclic aliphatic, carbocyclic and heterocyclic aromatic structures. The X-R compounds with acid hydrogen are excluded. The next step is to bring the organic compound X-R into contact with fluoride ions which are present in a solvent. These fluoride ions are essentially carrier free  18  F ions. The organic compound is brought into contact with the fluoride ions in an apparatus to produce a reaction. The reacting mixture comes into contact during reaction only with surfaces in the apparatus which are made of metals as copper, stainless steel, platinum and Inconel and preferably of glassy carbon. In one embodiment, the reaction takes place at a temperature of between 100° C. and 150° C. in the presence of a basic alkali salt which is contained in a acetamide melt. The reaction may alternately take place in a preferred embodiment, in solution, in a moderately polar, aprotic solvent in the presence of a macrocyclic polyether and an alkali salt at a temperature in the range of 50° C. to 150° C.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates generally to ¹⁸ F labeling of organic compoundsand, more particularly, to a process for the production of ¹⁸ F-labeledorganic compounds by nucleophilic exchange.

2. Description of the Prior Art

The production of compounds labeled with fluorine-18 has for years beenthe focus of radiopharmaceutical research for nuclear medicine andfunctional diagnosis. This is because of the optimal nuclear propertiesof fluorine-18 for positron emission tomography (PET). The positronemitter, fluorine-18, is more advantageous to use in many applicationsthan other radionuclides, as a means by which covalently-bonded fluorinecompounds can be labeled. Fluorine-18, because of its decay energy (0.64MeV), allows the highest inherent resolution during PET measurements(without interfering secondry lines). In addition, fluorine-18 has arelatively convenient half life, T_(1/2), of 109.7 minutes.

Carrier-free or labeled compounds of extremely high specific activity ofmore than 1000 curies/mmol are especially necessary for in vivo receptorstudies, and in all cases where, for toxicological reasons or not todisturb sensitive biological equilibria, an in vivo application in thesubnanomolar or picomolar region is necessary. Electrophilic processeshave all recently been based on labeled molecular fluorine (F₂).However, the molecular fluorine inherently contains inactive fluorinecarriers with the resultant problems ensuing therefrom. The nucleophilicsubstitution with fluoride essentially makes possible an introduction of¹⁸ F without or if any only extremely small quantities of carriersubstances. The problems of reactions with fluoride lie in its extremelyhigh charge density and hydrophilic properties, which cause a weaknucleophilic action and high adsorption losses, especially when workingwithout a carrier additive. Reactions which utilize carrier-freefluoride therefore generally require the careful exclusion of water.

Previous investigations have attempted to increase the reactivity ofammonium or alkali fluorides by the addition of phase transfer catalyst,such as long-chain onium salts and cyclic polyethers (crown ethers), orby the addition of silver oxide, as well as by the use ofeasily-substitutable leaving groups such as tosylates and triflates.Except for a few cases, production without the addition of carriers wasso far possible only with simple alkyl compounds, and even then producedonly small yields (less than 20%). Higher yields were obtained only withfluoroethanol, methyl fluoride and simple aromatic molecules,substituted benzols, with the latter by the replacement of thenitro-group in DMSO, at relatively high temperatures of 150° C. withRb¹⁸ F. DMSO is dimethyl sulfoxide, which is described in U.S. Pat. No.4,514,377, which patent is incorporated herein by reference.

OBJECT OF THE INVENTION

The object of the invention is therefore to increase the yields of ¹⁸ Fcompounds when processed carrier-free or without carriers(no-carrier-added). This object is primarily achieved by thenucleophilic substitution reaction being conducted in an apparatus whichhas surfaces with which the reaction mixture comes into contact whichare made from predetermined metals such as copper, platinum, stainlesssteel, Inconel® (Ni base alloys manufactured by INCO, Canada), or mostpreferably from glassy or vitreous carbon glass (pyro carbon) such asSigradur® G, L or K. Sigradur carbon glasses are manufactured by SigriElektrographit GMBH, Meitingen, Federal Republic of Germany. Thesuperscript® indicates that the item is identified by a trademark whichis registered in a trademark register.

SUMMARY OF THE INVENTION

The invention resides broadly in a process for labeling organiccompounds with fluorine 18, the process comprising the steps of:providing an organic compound having a formula of X-R, wherein R is anarbitrarily substituted hydrocarbon structure being selected from thegroup consisting of aliphatic, alicyclic, heterocyclic aliphatic,carbocyclic and heterocyclic aromatic structures substituted whateverbut excluding H-acid compounds, wherein X is a nucleophilic leavinggroup; and contacting said organic compound with fluoride ions in asolvent, wherein the fluoride ions are essentially free ions, theorganic compound being contacted with the fluoride ions in an apparatus,all surfaces of which making contact with the reaction mixture, consistof predetermined metal or especially of glassy carbon whereby compoundshaving the formula ¹⁸ F-R are produced.

The predetermined metal may be selected from the group consistingessentially of copper, stainless steel, platinum and Inconel.

Yet another aspect of the invention deals with the above process whereinX is selected from the group consisting of halogens and pseudohalogensand when R is an aliphatic hydrocarbon structure especially of -OTos and-OTf, where Tos is tosylate and Tf is triflate or else. Tosylate isdescribed in U.S. Pat. No. 4,515,972, which is incorporated herein byreference. Triflates are described in U.S. Pat. No. 4,001,291, which isalso incorporated herein by reference. An example of a pseudohalogen isa cyanogen.

A further aspect of the invention deals with the above process wherein Ris an aromatic hydrocarbon structure; in this case X preferably may beselected from -NO₂ and -N⁺ (alkyl)₃.

A yet further aspect of the invention deals with the above processwherein the solvent is an acetamide liquified material containing abasic alkali salt.

An additional aspect of the invention deals with the above processwherein said basic alkali salt is a member of the group consisting ofNa₂ CO₃, K₂ Co₃, Rb₂ CO₃ and Cs₂ CO₃.

An additional further aspect of the invention deals with the aboveprocess wherein the organic compound is contacted with the fluoride ionsbetween about 100° C and about 150° C.

A yet additional aspect of the invention deals with the above processwherein the solvent is a moderately polar, aprotic solvent which furthercontains the complex of a basic nonnucleophile alkali salt andmacrocyclic polyether.

Another aspect of the invention deals with the above process wherein thepolyether is an aminopolyether.

Yet another aspect of the invention deals with the above process whereinthe aminopolyether is a 2.2.2 aminopolyether and the salt is K₂ CO₃.

A further aspect of the invention deals with the above process whereinthe organic compound is contacted with the fluoride ions in themoderately polar, aprotic solvent at between about 50° C. and about 150°C.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The reaction is thereby preferably conducted either in liquefiedacetamide material containing a basic alkali salt, specifically Na₂ CO₃,K₂ CO₃, Rb₂ CO₃ or Cs₂ CO₃ at 100° to 150° C., or preferably at 50° to150° C. in a homogeneous phase with an aminopolyether, such asKryptofix® 2 2 2, - complexed K₂ CO₃, especially in acetonitril and/orDMSO as a solvent. Kryptofix® is manufactured by Merck, Darmstadt,Federal Republic of Germany.

According to the invention, secondary reactions are prevented, walllosses are almost completely eliminated, and surprisingly high yields(up to 95%) are achieved. The reaction in aprotic solvents withaminopolyether is also only insignificantly adversely affected by tracesof water. Such traces of water are herein meant to include quantities ofup to about 1%.

The invention comprises the following improvements:

1. Exclusion of Adsorption Losses

Since high adsorption losses always occur in the reaction of fluoridewithout the addition of a carrier, the total yield, in relation to the¹⁸ F fluoride produeed in the reactor or accelerator, is sometimesdrastically reduced. Systematic studies of various wall materials forreaction vessels showed that copper, stainless steel and Inconel® resultin approximately 10% wall losses, and glassy carbon results in less than2% wall loss. The use of these materials, especially of glassy carbon,made possible ¹⁸ F fluorination without a carrier of the above compoundswith--up to now not achieved--total radiochemical yields of 60-95% underless violent reaction conditions than heretofore. The use of glassycarbon was shown to be especially desirable because of the very low wallloss. Fluorinations in inert vessels usually used heretofore, such asTeflon, likewise may result in low wall losses, but lead to lowerexchange yields. When Teflon is used, the poor handling and the low heatconductivity of the material are causes of longer synthesis times andthus a loss of radioactivity.

2. Improvement of the Conversion

(a) By the addition of basic alkali salts of low nucleophilic action,specifically Na₂ Co₃, K₂ CO₃, Rb₂ CO₃, Cs₂ CO₃ to liquefied acetamidematerial at 100°-150° C., the exchange of the dissolved fluoride couldbe increased, without the addition of a carrier with alkyl compounds,especially with compounds comprising long-chain ω-halogen fatty acidsand suitably-protected sugars, from 0% to 70% radiochemical yields.Significant ¹⁸ F-labeled radiopharmaceuticals for use with PET are knownand available in both long-chain ω-halogen fatty acids andsuitably-protected sugar compounds--see examples herein.

(b) As a most preferred alternative, in a homogeneous solution of(optimal) acetonitril, which contained a complex of aminopolyether2.2.2. (Kryptofix®) with K₂ CO₃, 60% to 95% of carrier-free ¹⁸ Ffluoride was converted with these same alkyl compounds during reflux.The special suitability of this reaction mixture lies in the optimalcation-polyether combination and the use of equimolar quantities ofaminopolyether and alkali cations. In addition to the cation-polyethercombination, complexes of other metal cations and correspondingpolyethers were similarly well suited for the reaction.

These reaction solutions as described above in (a) and (b) are likewisesuited for nucleophilic fluorine exchange with aromatic compounds,whereupon, in comparison with prior methods, significant advantages ofthe present invention are represented in that, other than --NO₂,halogens may be used as the leaving groups. A further advantage of theprocess is the lower reaction temperature. This feature of the inventionis especially important for the carrier-free production of complex ¹⁸F-labeled receptor ligands for the in vivo measurement of receptordensities by means of PET. One important example is neuroleptics of thebutyrophenon series, such as spiroperidol, methylspiroperidol,benperidol, etc., which have one fluorine atom in the pharmocophoricgroup. The specific activities to be attained for all the compuundsdescribed are greater than 1.5×10⁴ curies/mmol.

Some examples of positron emission tomography are described in U.S. Pat.Nos. 4,415,807; 4,352,018; 4,309,611; and 4,150,292, which patents areincorporated herein by reference.

EXAMPLES Example 1

[¹⁸ F]-17-Fluoroheptadecanoic acid (17-¹⁸ F-HdA) where HdA meansfluoroheptadecanoic acid.

for A: acetamide melt

2-5 ml of twice-distilled water containing ¹⁸ F-ions and 10 mg K₂ CO₃were evaporated until dry at 180° C. in a helium flow (approximately 50ml min) in a cylindrical Sigradur®-G vessel with a capacity ofapproximately 10 ml, and then heated for another 15 minutes at 180° C.in the helium flow and then cooled in the helium flow. 100 mg ofacetamide and 20-120 mg 17-bromine-heptadecanoic acid methylester wereadded. The reaction vessel is closed by means of a V4A type stainlesssteel plug and a Sigraflex® gasket. Sigraflex is manufactured by SigriElektrographit GMBH, Meitingen, Federal Republic of Germany. Thereaction time was 10-20 minutes at 100°-150° C. in an oil bathaccompanied by agitation. After cooling, 2 ml of 5n methanolic KOH wereadded, and then the agitated mixture was heated for 15 minutes at 70° C.in an oil bath.

After addition of 10 ml H₂ O and 3 ml 15% H₂ SO₄, repeated extractionwith 10 ml or 5 ml n-heptane at 80° C. was performed. The heptane phasesare vaporized until dryness and the [¹⁸ F]-17-fluoroheptadecanoic acidtransferred in 2 ml eluent and isolated by means of high-pressure liquidchromotography.

High pressure liquid chromotography is described in the work of the samename authored by Phyllis Brown; published by Academic Press, 1973, andis incorporated herein by reference. Liquid chromotography is describedin U.S. Pat. No. 4,392,996, which is also incorporated herein byreference.

High pressure liquid chromotography (HPLC) was performed in achromotography column filled with Nucleosil C-18 which had a grain sizeof 7.5 μm. Nucleosil C-18 designates a filling on a base of silica gel,derivated with a C-18 alkyl. The chromotography column has a length of25 cm and an inner diameter of 16 mm. The solution used was methanol,water, and acetic acid in a volume ratio of 896 parts methanol, to 100parts water, to 4 parts acetic acid. The chromotography was carried outat a pressure of 43 bars and at a flow rate of 7.4 ml/min. k' (17-F-HdA)was equal to 2.64. This resulted in a yield of 17-¹⁸ F-HdA being 48±4%.This high pressure chromotography may be expressed in abbreviated formas follows:

Nucleosil C-18, 7.5 m; 25 cm; 16 mm i. φ; methanol: Water: acetic acid896:100:4 (v,v,v); 43 bar; 7.4 ml/min; k' (17-F-HdA) =2.64

Yield of 17-¹⁸ F-HdA: 92±3% Nucleosil® is manufactured by Macherey Nagel& Co., Duren, Federal Republic of Germany.

EXAMPLE 2

For B: Aminopolyether acetonitril solution

2 to 5 ml of twice-distilled water containing ¹⁸ F-ions and 2.3 mg K₂CO₃ and 12.6 mg aminopolyether 2.2.2 were placed in a cylindricalSigradur®-G vessel with a capacity of approximately 10 ml. At an oilbath temperature of approximately 110° C. and a temperature ofapproximately 90° C. in the reaction vessel, the solution is evaporateduntil dry in a helium flow of approximately 50 ml/min. Then 0.5 ml CH₃CN, (spectroscopically pure; dried over Al₂ O₃, activity level I,active, neutral) and 10 mg 17-bromineheptadecanoic acid methylester areadded and boiled in reflux for 10 minutes. Then there is an addition of2 ml 5 n methanol KOH and reflux boiling for 15 minutes. The furtherpreparation was as described for the acetamide melt from Example 1 asfollows: After addition of 10 ml H₂ O and 3 ml 15% H₂ SO₄ , repeatedextraction with 10 or 5 ml n-heptane at 80° C. was performed. Theheptane phases were vaporized until dry and the [¹⁸F]-17-fluoroheptadecanoic acid transferred in 2 ml eluent and wereisolated by means of high-pressure liquid chromotography.

Yield: 92±3%.

EXAMPLE 3

[¹⁸ F]-2-fluoro-2-desoxy-D-glucose (2-¹⁸ FDG) where FDG signifiesfluoro-2-desoxy-D-glucose

for B: Aminopolyether-acetonitril solution

The water containing ¹⁸ F- was evaporated until dryness, as described inExample 2, in the presence of 2.2.2 aminopolyether and K₂ CO₃. Then asolution of 20 mg1.3.4.6-tetra-0-acetyl-2-O-trifluormethanesulfonyl-β-D-mannopyranose(dried preferably over Sicapent) in 1 ml acetonitril (see Example 2) wasadded and heated to boiling for 5 minutes. Then the solution wasevaporated to approximately 0.5 ml in a helium flow and after dilutionwith about 5 ml water permeated through a SEP-PAK C₁₈ cartridge. Theproduct/educt mixture was extracted with 2 ml THF (tetrahydrofuran) fromthe cartridge and the THF evapoated until dryness. The residue washydrolyzed after the addition of 2 ml 1 molar hydrochloric acid for 15minutes in reflux. To clean the product from hydrophobic by-products,HCl and unreacted ¹⁸ F⁻, the solution of 2-¹⁸ FDG was filtered by meansof a C₁₈ SEP PAK cartridge and then subjected to chromotogrpphy via ashort column with ion-retarding resin (AG 11A8, BioRad) and aluminumoxide. Yield: 82±4%. SEP PAK is manufactured by Waters Associates, MapleStreet, Melfort, Massachusetts 01757. AG 11A8, BioRad is manufactured byBioRad, Chemical Division, 200 Wright Avenue, Richmond, Calif. 94804.

The invention as described hereinabove in the context of the preferredembodiments is not to be taken as limited to all of the provided detailsthereof, since modifications and variations thereof may be made withoutdeparting from the spirit and scope of the invention.

What is claimed is:
 1. A process for labeling organic compounds withfluorine 18, said process comprising the steps of:(a) providing anorganic compound having a formula:

    X-R

wherein R is an arbitrarily substituted hydrocarbon structure, saidhydrocarbon structure being selected from a member of the groupconsisting of aliphatic, alicyclic, heterocyclic aliphatic, carbocyclicand heterocyclic aromatic structures substituted wherever but excludingH-acid compounds, wherein X is a nucleophilic leaving group; and (b)contacting said organic compound with fluoride ions in a solvent,wherein said fluoride ions are essentially carrier free ¹⁸ F ions; saidsolvent being a moderately polar, aprotic solvent which further containshomogeneously dissolved therein the complex of a basic non-nucleophilealkali salt and macrocyclic polyether.
 2. The process as in claim 1wherein said macrocyclic polyether is an aminopolyether.
 3. The processas in claim 2 wherein said aminopolyether is a 2.2.2 aminopolyether. 4.The process as in claim 3 wherein said salt is K₂ CO₃.